Nonenzymatic gluconeogenesis-like formation of fructose 1,6-bisphosphate in ice

Proc Natl Acad Sci U S A. 2017 Jul 11;114(28):7403-7407. doi: 10.1073/pnas.1702274114. Epub 2017 Jun 26.


The evolutionary origins of metabolism, in particular the emergence of the sugar phosphates that constitute glycolysis, the pentose phosphate pathway, and the RNA and DNA backbone, are largely unknown. In cells, a major source of glucose and the large sugar phosphates is gluconeogenesis. This ancient anabolic pathway (re-)builds carbon bonds as cleaved in glycolysis in an aldol condensation of the unstable catabolites glyceraldehyde 3-phosphate and dihydroxyacetone phosphate, forming the much more stable fructose 1,6-bisphosphate. We here report the discovery of a nonenzymatic counterpart to this reaction. The in-ice nonenzymatic aldol addition leads to the continuous accumulation of fructose 1,6-bisphosphate in a permanently frozen solution as followed over months. Moreover, the in-ice reaction is accelerated by simple amino acids, in particular glycine and lysine. Revealing that gluconeogenesis may be of nonenzymatic origin, our results shed light on how glucose anabolism could have emerged in early life forms. Furthermore, the amino acid acceleration of a key cellular anabolic reaction may indicate a link between prebiotic chemistry and the nature of the first metabolic enzymes.

Keywords: evolution; gluconeogenesis; metabolism; nonenzymatic reactions; origin of metabolism.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acids / chemistry
  • Fructose-Bisphosphate Aldolase / chemistry
  • Fructosediphosphates / metabolism*
  • Gluconeogenesis*
  • Glucose / chemistry
  • Glycolysis
  • Hydrogen-Ion Concentration
  • Ice*
  • Magnetic Resonance Spectroscopy
  • Pentose Phosphate Pathway
  • Phosphorylation
  • Sugar Phosphates / chemistry
  • Temperature
  • Time Factors


  • Amino Acids
  • Fructosediphosphates
  • Ice
  • Sugar Phosphates
  • Fructose-Bisphosphate Aldolase
  • Glucose
  • fructose-1,6-diphosphate